Cell sheet formation enhances the therapeutic effects of human umbilical cord mesenchymal stem cells on myocardial infarction as a bioactive material

Abstract

Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades. However, optimal cell types and transplantation methods remain unclear. This study evaluated the therapeutic effects of human umbilical cord mesenchymal stem cell (hUCMSC) sheet on myocardial infarction (MI). Methods hUCMSCs expressing luciferase were generated by lentiviral transduction for in vivo bio-luminescent imaging tracking of cells. We applied a temperature-responsive cell culture surface-based method to form the hUCMSC sheet. Cell retention was evaluated using an in vivo bio-luminescent imaging tracking system. Unbiased transcriptional profiling of infarcted hearts and further immunohistochemical assessment of monocyte and macrophage subtypes were used to determine the mechanisms underlying the therapeutic effects of the hUCMSC sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, angiogenesis and left ventricular remodelling. Results When transplanted to the infarcted mouse hearts, hUCMSC sheet significantly improved the retention and survival compared with cell suspension. At the early stage of MI, hUCMSC sheet modulated inflammation by decreasing Mcp1-positive monocytes and CD68-positive macrophages and increasing Cx3cr1-positive non-classical macrophages, preserving the cardiomyocytes from acute injury. Moreover, the extracellular matrix produced by hUCMSC sheet then served as bioactive scaffold for the host cells to graft and generate new epicardial tissue, providing mechanical support and routes for revascularsation. These effects of hUCMSC sheet treatment significantly improved the cardiac function at days 7 and 28 post-MI. Conclusions hUCMSC sheet formation dramatically improved the biological functions of hUCMSCs, mitigating adverse post-MI remodelling by modulating the inflammatory response and providing bioactive scaffold upon transplantation into the heart. Translational perspective Due to its excellent availability as well as superior local cellular retention and survival, allogenic transplantation of hUCMSC sheets can more effectively acquire the biological functions of hUCMSCs, such as modulating inflammation and enhancing angiogenesis. Moreover, the hUCMSC sheet method allows the transfer of an intact extracellular matrix without introducing exogenous or synthetic biomaterial, further improving its clinical applicability.

Human endometrium-derived stem cell improves cardiac function after myocardial ischemic injury by enhancing angiogenesis and myocardial metabolism

“…6 a, b). To assess blood vessel formation, arteriole and capillary densities were quantified by α-SMA and isolectin staining, respectively [ 18 ]. Arteriolar density was significantly higher among the hEMSC group compared to hBMSC in the border zone of the infarct, and both were also significantly higher than the PBS control group.…”

“…Nevertheless, future long-term safety studies are necessary for screening out any potential tumorigenic cells from endometrial samples before therapeutic use. Furthermore, there are some technical shortcomings in this study, such as hEMSCs being quantified by RFP labeling, rather than a more sensitive in vivo bioluminescent imaging technique better-equipped to track cell retention in live animals, as well as measuring cardiac function based on the short-axis, which is more prone to human error than the LV long-axis method [ 18 ]. Lastly, future studies with larger sample sizes should be performed to confirm the presence of key differences in protein/mRNA expression levels behind the cardio-protective effects of hEMSCs.…”

Stem Cell-Based Therapy for Diabetic Foot Ulcers

“…It uses temperature-sensitive culture systems or enzyme-sensitive culture systems to naturally desorb cells from the substrate surface and eventually obtain a cell sheet layer structure containing ECM (Zhou et al, 2020). The cell sheet technology can avoid immune rejection caused by exogenous foreign substances such as scaffold materials and maintain the threedimensional structure of the ECM (Guo et al, 2021). Stem cells, as potential cells with strong regenerative capacity, are the best choice for tissue engineering cell sheets to play a role in damage repair.…”

Application of mesenchymal stem cell sheet to treatment of ischemic heart disease

“…UC-MSC sheets also significantly promoted angiogenesis, reduced fibrosis, and modulated post-MI inflammation, thereby improving cardiac function. Researchers also found that inflammation was modulated by decreasing Mcp1-positive monocytes and CD68-positive macrophages and increasing Cx3cr1-positive non-classical macrophages [ 33 ]. Recently, the BOE Regenerative Medicine Technology team has verified the effectiveness of human UC-MSC sheets in a porcine chronic myocardial ischemia model.…”

“…The application of UC-MSC sheets can also convert the use pattern from individual medical technology to a “live medicine,” which could be regulated in a good manufacturing practice (GMP) system. The feasibility and safety of UC-MSC sheets have been tested in animal models of myocardial infarction [ 33 ]. More clinical study and clinical trials are necessary to confirm UC-MSC sheets to be a safe and effective therapeutic approach for clinical application.…”